Feedback Control of Bifurcations in Spatially-Extended Cardiac Muscle

在这个多学科的项目中，来自生物医学工程、儿科心脏病学、物理学和数学的研究人员将结合理论和实验方法来研究快速起搏下心脏反应的稳定性。随着起搏频率的增加，心肌表现出动作电位时程的间歇性变化(时程交替)。动作电位交替及其临床表现T波交替与心律失常的易感性增加有关。因此，通过拟议的研究增加对节律稳定性的了解，将导致开发新的技术来检测心律失常的前兆，并识别有纤颤和心动过速风险的患者。具体目标是：(1)开发一种新的、更强大的实验方案来确定心脏反应模式的稳定性。(2)研究在空间扩展的均匀组织中出现的稳态交替是否总是不协调的(即，组织某些区域的时程振荡与起搏部位的振荡异相)。(3)构建基于光纤的跨壁标测系统，实现三维标测动作电位。这项研究将从使用理想化的膜动力学模型的数学分析开始。分析结果将通过计算机模拟进行检验，首先涉及空间夹持条件下的理想化膜模型，然后发展到高达3个空间维度的生理精确膜模型。一些模型还将考虑跨室壁心动过速的异质性。同时，分析结果将进行实验验证。最初的测试将使用牛蛙脑室的体外制剂，这是相对的，并进展到兔脑室的体外楔形制剂，它表现出哺乳动物心脏典型的跨壁动作电位不均质性和各向异性。理论、计算机模拟和实验研究结果之间的三向比较将使我们能够改进并在必要时扩展数学理论和计算机模型，每次迭代都会导致对心脏动力学的更全面的了解。

In this multidisciplinary project, researchers from Biomedical Engineering, Pediatric Cardiology, Physics, and Mathematics will combine theoretical and experimental approaches to investigate the stability of cardiac response under rapid pacing. As the pacing rate increases, cardiac muscle exhibits beat-to-beat changes in the action potential duration (APD alternans). APD alternans and its clinical manifestation, T-wave alternans, are associated with increased vulnerability for arrhythmias. Thus, increased understanding of the rhythm stability coming from the proposed research will lead to the development of new techniques for detection of the precursors of arrhythmias and for identifying patients at risk for fibrillation and tachycardias. Specific Aims are: (1) Develop a new, more robust experimental protocol for determining stability of the cardiac response pattern. (2) Investigate whether steady-state alternans occurring in spatially extended, homogeneous tissue is always discordant (i.e., APD oscillations in some regions of the tissue are out of phase with the oscillations at the pacing site). (3) Construct an optical fiber-based transmural mapping system that allows mapping action potentials in three dimensions. The research will start with mathematical analysis that uses idealized models of membrane kinetics. Analytical results will be tested through computer simulations, first involving idealized membrane models under space clamp conditions, then progressing to physiologically accurate membrane models in up to three spatial dimensions. Some models will also take into account transmural APD heterogeneity. Concurrently, analytical results will be tested experimentally. Initial tests will use in-vitro preparations of bullfrog ventricle, which are relatively, and progress to in-vitro wedge preparations of rabbit ventricle, which exhibit transmural APD heterogeneity and anisotropy typical for mammalian hearts. The three-way comparisons between results from theory, computer simulations, and experimental studies will allow us to refine and, if needed, expand the mathematical theory and computer models, with each iteration leading to more complete understanding of cardiac dynamics.